Percutaneous preparations

ABSTRACT

A bisphosphonic acid derivative-containing percutaneous preparation of an excellent percutaneous permeability, comprising a bisphosphonic acid derivative such as incadronic acid, minodronic acid, etc., or pharmaceutically acceptable salts thereof, a solubilizing agent for the derivative or pharmaceutically acceptable salts thereof, and an amphiphilic solubilizing auxiliary agent, which may optionally contain a suspension-type base such as a polyvalent alcohol, a higher fatty acid ester, a liquid hydrocarbon or a vegetable oil, etc. This preparation has an excellent percutaneous permeability, reduces burdens on the patient, does not deteriorate the patient&#39;s compliance even in the administration over a prolonged period of time and can achieve the therapeutic effects in a short period of time.

TECHNICAL FIELD

The present invention relates to bisphosphonic acidderivative-containing percutaneous preparations having an excellentpercutaneous permeability, which comprises bisphosphonic acidderivatives or pharmaceutically acceptable salts thereof, and solventsfor the bisphosphonic acid derivatives or pharmaceutically acceptablesalts thereof and amphiphilic solubilizing auxiliary agents. Moreparticularly, the present invention relates to percutaneous preparationscomprising incadronic acid or minodronic acid, or pharmaceuticallyacceptable salts thereof.

BACKGROUND ART

Certain synthetic bisphosphonate compounds having a methanebisphosphonicacid structure which are structurally analogous to pyrophosphoric acidand stable also in vivo (hereinafter referred to as bisphosphonic acidderivatives or pharmaceutically acceptable salts thereof, or sometimesmerely as bisphosphonic acid derivatives) have biological actions suchas an excellent bone resorption inhibitory action, ectopic calcificationinhibitory action, etc. and are useful as agents for the treatment ofdiseases associated with accelerated bone resorption, ectopiccalcification, etc., e.g., osteoporosis, Paget's disease of bone,hypercalcemia accompanied by malignant tumor, etc. Some of them havealready been used clinically.

As bisphosphonates commercially available so far and currently underdevelopment, there are known alendronate, ibandronate, incadronate,etidronate, olpadronate, clodronate, zoledronate, tiludronate,neridronate, pamidronate, risendronate, minodronic acid[1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethylidenebisphosphonic acid],disodium 1-hydroxy-3-(1-pyrrolidinyl)propylidenebisphosphonate, etc.

In particular, incadronic acid or minodronic acid or pharmaceuticallyacceptable salts thereof including incadronate (disodium incadronate) orminodronic acid have a potent bone resorption inhibitory action, anexcellent anti-inflammatory action and antipyretic analgesic action, andare useful for diseases such as hypercalcemia, etc., caused by boneresorption (JP-B-6-99457 and JP-B-7-629).

Pharmacokinetic studies on tiludronate, pamidronate, etidronate,clodronate and alendronate have been extensively made. It is reportedthat these bisphosphonates are poor in bioavailability when orallyadministered, should avoid alimentary effects since their absorption issuppressed especially in the presence of calcium or iron, deposit veryrapidly onto bone and might cause gastrointestinal disorders by oraladministration though they are mild, and further that recent studiesrevealed bioavailability of the bisphosphonates even when administeredpernasally or percutaneously, and so on (see “Bisphosphonates and BoneDisease: Kiso-to-Rinsho (The Clinical Report)” Jul. 30, 1996, publishedby Ishiyaku Publishers Inc.).

On the other hand, British Patent No. 1,582,694 discloses a compositionsuitable particularly for topically treating the anomalous mobilizationand deposition of calcium phosphate salts in the tissues of humans andlower animals, including percutaneous administration, which comprises asafe and effective amount of an organophosphonate compound incombination with a carrier containing a safe and effective amount of anorganosulfoxide compound as a specific penetration enhancer.Particularly in the patent supra, a composition composed of etidronateor clodronate, decyl methyl sulfoxide, water, or a cream basepenetrating carrier composed of water, ethanol, stearyl alcohol andlanolin is shown as a specific example of formulations. It is describedin the patent that a typical organosulfoxide compound, decyl methylsulfoxide, enhanced especially in the skin permeation test in vitro byabout 6-fold the penetration effect of etidronate, which is a typicalexample of the organophosphonates, as compared to control; in the invivo tests with rats to verify therapeutic effects ondihydrotachysterol-induced calcification (calciphylaxis), a skin calciumlevel (%) was 0.035 in the normal control and 0.067 in the control withetidronate alone dissolved in the penetrating carrier vehicle, whereasthe skin calcium level was enhanced to 2.026 when treated with acomposition composed of etidronate and a penetrating carrier containingdecyl methyl sulfoxide.

U.S. Pat. No. 5,133,972 also discloses a pharmaceutical preparation fortopical application, which comprises a particular methanediphosphonicacid represented by formula (I) below:

(wherein . . . Het1 is unsubstituted or substituted, monocyclic, 5- or6-membered monoaza-, diaza- or thiaza-aryl that is bonded via a ringcarbon atom, or R₁ is . . . hydroxy group, R₂ is -A-R₃, in which A is analkylene group and, on the one hand, R₃ is Het2, which is Het1 bondedvia a ring carbon or ring nitrogen atom, or, . . . ) (As to furtherdetailed definitions, please see the above-mentioned U.S. Patentspecification) or pharmaceutically acceptable salts thereof. Accordingto the above-mentioned Specification, it is described that “it wasdiscovered that pharmaceutically acceptable methanebisphosphonic acids,especially those of formula I below, are readily conveyed through theskin and can thus immediately act systemically,” indicating that theseunexpected discoveries were made during the particular studies in vitro.Though the test method is described in detail, any data concerningpercutaneous permeability is not disclosed at all. The above-mentionedSpecification merely describes various formulations of zoledronatespecifically.

Incadronic acid, the chemical structure of which is characterized inbinding its cycloheptane ring at the 1-position not via a lower alkylenegroup, or pharmaceutically acceptable salts thereof and the saidminodronic acid, the chemical structure of which is characterized inhaving the imidazopyridine ring which is not a monocyclic hetero-ringbut a bicyclic hetero-ring, or pharmaceutically acceptable salts thereofare not included in the chemical formula I described in the U.S. patent.

Thus, any specific percutaneous preparation which contains as theeffective ingredient incadronic acid or minodronic acid, orpharmaceutically acceptable salts thereof is unknown so far.

In these bisphosphonates, pamidronate or the like is made available asan oral preparation. However, the bisphosphonates are poor inabsorbability per os and sometimes cause an undesired effect such asgastrointestinal disorders, etc. when a large dose is administered. Inpractice, the bisphosphonates are administered as injections. In theform of injections, pain is attendant and patients' compliance islowered where prolonged administration is required. Especially, abisphosphonate having a weak effect is often administered continuouslyover a prolonged period of time. Under these situations, a great demandstill exists to develop a preparation with a minimized burden on thepatient without deteriorating patients' compliance even whenadministered over a long period of time. It is also earnestly desired todevelop a preparation capable of achieving therapeutic effects in ashort period of time.

DISCLOSURE OF THE INVENTION

Under such a technical level, the present inventors made extensivestudies to develop pharmaceutical preparations of incadronate, which iscalled the bisphosphonate of the third generation, without relying onoral administration, injections such as intravenous drip infusion, etc.As a result, it has been found that incadronate shows an excellentpercutaneous permeability and targeting toward bone tissues and at thesame time, excellent drug retention in bone tissues which was unexpectedfrom conventional findings on the bisphosphonates.

The present inventors further performed similar tests also on minodronicacid and unexpectedly found that minodronic acid shows the same effectas in incadronate, although minodronic acid is a compound havingproperties that is practically insoluble in water unlike incadronate,insoluble even in an organic solvent and soluble in an alkaline solvent.Based on the finding, it has been attained for the first time to providepercutaneous preparations comprising as the effective ingredientincadronic acid or minodronic acid, or pharmaceutically acceptable saltsthereof.

The present inventors made further investigations on thesebisphosphonates to optimize percutaneous absorption preparations andfound that extremely high percutaneous permeability is shown in thesystem where a suspension-type base is used.

The present inventors made further extensive studies to clarify causesfor high permeability when using the suspension-type base. As a result,it has been demonstrated that when an amphiphilic solubilizing auxiliaryagent soluble in both water and oil is formulated in the percutaneousdrug system, a more excellent percutaneous permeability is exhibitedthan the preparations formulated with decyl methyl sulfoxide describedin the British Patent No. 1,582,694 supra and known to promote aparticularly excellent percutaneous permeability, and the formulationcontaining this amphiphilic solubilizing auxiliary agent shows effectsnot only on the bisphosphonates such as incadronate or minodronic acidbut also on the other bisphosphonates in a similar fashion.

It has also been demonstrated that the percutaneous preparation ofminodronic acid formulated with the amphiphilic solubilizing auxiliaryagent shows a percutaneous permeability enhanced by several-fold, whencompared to a similar percutaneous preparation of alendronate. As such,it is an unexpectedly marked effect in the art to differ in thepercutaneous permeability by several times between the preparations ofthe same preparation materials except for the effective ingredient andamong the bisphosphonates, minodronic acid, etc. were recognized to beparticularly useful in providing excellent percutaneous preparations.

The present invention has been accomplished based on these findings andrelates to:

(1) a bisphosphonic acid derivative-containing percutaneous preparationhaving an excellent percutaneous absorption, which comprises abisphosphonic acid derivative or a pharmaceutically acceptable saltthereof, a solubilizing agent for the bisphosphonic acid derivative or apharmaceutically acceptable salt thereof, and an amphiphilicsolubilizing auxiliary agent;(2) the percutaneous preparation according to (1), wherein apercutaneously effective dose of the bisphosphonic acid derivative or apharmaceutically acceptable salt thereof, and 0.01 to 10 parts by weightof the solubilizing agent for the bisphosphonic acid derivative or apharmaceutically acceptable salt thereof based on 1 part by weight ofthe bisphosphonic acid derivative or a pharmaceutically acceptable saltthereof and 1 to 10 parts by weight of the amphiphilic solubilizingauxiliary agent based on the whole preparation are formulated;(3) the percutaneous preparation according to (1) or (2), which containsa suspension-type base;(4) the percutaneous preparation according to (3), wherein thesuspension-type base is a polyvalent alcohol, a higher fatty acid ester,a liquid hydrocarbon or a vegetable oil;(5) the percutaneous preparation according to (4), wherein a compoundingamount of the suspension-type base is 0.01 to 50 wt % based on the wholepreparation;(6) the percutaneous preparation according to any one of (1) through(5), wherein the bisphosphonic acid derivative or a pharmaceuticallyacceptable salt thereof is at least one selected from the groupconsisting of alendronic acid, ibandronic acid, incadronic acid,etidronic acid, olpadronic acid, clodronic acid, zoledronic acid,tiludronic acid, neridronic acid, pamidronic acid, risendronic acid,minodronic acid and 1-hydroxy-3-(1-pyrrolidinyl)propylidenebisphosphonicacid as well as pharmaceutically acceptable salts thereof;(7) the percutaneous preparation according to (6), wherein thebisphosphonic acid derivative or a pharmaceutically acceptable saltthereof is incadronate or minodronic acid;(8) the percutaneous preparation according to (7), wherein thesolubilizing agent for the bisphosphonic acid derivative or apharmaceutically acceptable salt thereof is water or alkaline water;(9) the percutaneous preparation according to any one of (1) through(8), wherein the amphiphilic solubilizing auxiliary agent is a glycerinefatty acid ester, a polyglycerine fatty acid ester, a sorbitan fattyacid ester, a polyoxyethylene sorbitan fatty acid ester, apolyoxyethylene sorbitol fatty acid ester, a polyoxyethylenealkyl-formaldehyde adduct, a polyoxyethylene sterol/hydrogenated sterol,a polyethylene glycol fatty acid ester, a polyoxyethylene alkyl ether, apolyoxyethylene polyoxypropylene alkyl ether, a polyoxyethylenepolyoxypropylene glycol, a polyoxyethylene alkyl phenyl ether, a yellowbeeswax derivative, a polyoxyethylene alkylamine/fatty acid amide, apolyoxyethylene alkyl ether phosphoric acid/phosphate, a monofatty acidpolyoxyethylene-hydrogenated castor oil, N-methyl-2-pyrrolidone,acetone, methyl ethyl ketone, methyl isobutyl ketone, triethyl citrate,ethyl acetate, ethyl lactate, triacetine, pantothenyl ethyl ether,ethylene glycol monobutyl ether, dimethyl ether, isopropanolamine,diisopropanolamine, 2-amino-2-methyl-1-propanol,2-amino-2-methyl-1-propanediol, N,N-dimethylacetamide, geranioldenatured alcohol, sucrose octaacetate denatured alcohol, linalylacetate denatured alcohol, benzyl alcohol, butanol, 2-butanol,diethylene glycol, dipropylene glycol, 1,3-butylene glycol, propyleneglycol, propylene carbonate, thioglycolic acid, propionic acid,methanesulfonic acid, glacial acetic acid, lactic acid, butyric acid orichthammol;(10) the percutaneous preparation according to any one of (1) through(9), wherein a ratio of a soluble form to an insoluble form of thebisphosphonic acid derivative or a pharmaceutically acceptable saltthereof contained in the preparation is 1:0.01 to 1:0.9; and,(11) the percutaneous preparation according to any one of (1) through(10), wherein a liquid property of the solute of bisphosphonic acid andthe solubilizing agent is adjusted to the pH of 4 to 7.

The present invention further relates to:

(12) a percutaneous preparation comprising incadronic acid or minodronicacid, or a pharmaceutically acceptable salt thereof;

(13) the percutaneous preparation according to (12), which contains asuspension-type base;

(14) the percutaneous preparation according to (13), wherein thesuspension-type base is a polyvalent alcohol, a higher fatty acid ester,a liquid hydrocarbon or a vegetable oil;

(15) the percutaneous preparation according to (14), wherein acompounding amount of the suspension-type base is 0.01 to 50 wt % basedon the whole preparation;

(16) the percutaneous preparation according to any one of (12) to (15),wherein the preparation is in the form of a plaster formulation, anointment, a gel, an emulsion, a lotion or a liquid;

(17) the percutaneous preparation according to (16), wherein the form ofthe preparation is a plaster formulation; and,

(18) the percutaneous preparation according to (17), wherein the form ofthe preparation is a tape.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter the percutaneous preparation of the present invention isdescribed in detail.

The “percutaneous preparation” of the present invention is intended tomean a percutaneous preparation comprising incadronic acid or minodronicacid, or a pharmaceutically acceptable salt thereof, and a percutaneouspreparation comprising at least the bisphosphonic acid derivative or apharmaceutically acceptable salt thereof, the solubilizing agent for thebisphosphonic acid derivative or a pharmaceutically acceptable saltthereof and the amphiphilic solubilizing auxiliary agent.

The percutaneous preparation of the present invention comprisingincadronic acid or minodronic acid or a pharmaceutically acceptable saltthereof (hereinafter sometimes merely referred to as “the percutaneouspreparation comprising minodronic acid, etc.”) is composed of incadronicacid or minodronic acid or a pharmaceutically acceptable salt thereof,and a base for percutaneous administration. Particularly preferred isthe percutaneous preparation which contains the suspension-type base asone component of the base for percutaneous administration. Thepercutaneous preparation of the present invention containing minodronicacid, etc. is characterized by an excellent percutaneous permeability,targeting to the bone tissues and drug retention and furthercharacterized in that significant percutaneous permeability is exhibitedespecially in the presence of the suspension-type base. Thus, theinvention is useful as developing a new type of route for administrationof minodronic acid, etc.

The pharmaceutically acceptable salts of incadronic acid, which is oneof the effective ingredients in the percutaneous preparation of thepresent invention comprising incadronic acid or minodronic acid, orpharmaceutically acceptable salts thereof, are not particularly limitedso long as they are pharmaceutically acceptable salts that can attainthe objects of the present invention. However, disodium incadronate(hereinafter the disodium salt is referred to as incadronate) isespecially preferable. Turning to minodronic acid, it can be convertedinto the salt but is normally used in its free form.

The percutaneous preparation of the present invention containingminodronic acid, etc. does not prohibit compounding 2 or more ofincadronic acid, minodronic acid, or pharmaceutically acceptable saltsthereof to prepare the percutaneous preparation, or using in combinationwith other bisphosphonic acid derivatives or pharmaceutically acceptablesalts thereof to prepare the percutaneous preparation as the combineddrug. Herein, what is meant by the other “bisphosphonates” will beexplained later.

The compounding amount of minodronic acid, etc. as the effectiveingredients may be an effective dose pharmacologically required for thepercutaneous preparation. Especially the compounding amount of theeffective ingredient is somewhat different between incadronic acid orpharmaceutically acceptable salts thereof and minodronic acid orpharmaceutically acceptable salts thereof, and may also vary dependingon the forms of the percutaneous preparation, bases for percutaneousadministration used in the percutaneous preparation, their compoundingamounts, etc. Therefore, the compounding amount cannot be determined ingeneral but roughly speaking, is suitably in the range of 0.01 to 10 wt% and particularly preferably from 0.1 to 5 wt %, based on the wholepreparation. Where 2 or more effective ingredients are employed, it ispreferred that the combined amounts of these ingredients are within therange for formulation described above.

The “suspension-type base,” which is one of the bases for percutaneousadministration used in the percutaneous preparation of the presentinvention containing minodronic acid, etc. is not particularly limited,as long as it is a medicament that can significantly enhance thepercutaneous permeability when the skin permeation test is carried outusing a solution of the effective ingredients of the present inventionand is a suspension-type base capable of suspending the effectiveingredients of the present invention. Specifically, preferredsuspension-type bases include, for example, polyvalent alcohols such asethylene glycol, propylene glycol, butanediol, triethylene glycol,polyethylene glycol, glycerine, etc.; higher fatty acid esters having atleast 12 carbon atoms, such as hexyl laurate, butyl stearate, isopropylpalmitate, isopropyl myristate, octyldodecyl myristate, myristylmyristate, etc.; liquid hydrocarbons such as liquid paraffin, etc.; orvarious vegetable oils such as soybean oil, sesame oil, corn oil,linseed oil, sunflower oil, cotton seed oil, olive oil, castor oil,peanut oil, etc. These suspension-type bases exert the functions also assoftening agents when formulated as the components for a plasterformulation, etc.

The compounding amount of the suspension-type base may vary dependingupon the preparation form of percutaneous preparation, bases forpercutaneous administration used for the percutaneous preparation andtheir compounding amounts, solubility of drugs, etc. and cannot bedetermined in general. Roughly, the compounding amount is suitably 0.01to 50 wt % and preferably 0.1 to 40 wt %, based on the wholepreparation. When formulated as components in a plaster formulation,etc., these suspension-type bases also exhibit the function assofteners.

In the percutaneous preparation of the present invention containingminodronic acid, etc., it has been demonstrated that only byincorporating the amphiphilic solubilizing auxiliary agent laterdescribed especially without adding any percutaneous permeationpromoter, the preparation shows an excellent percutaneous permeabilityas compared to organosulfoxide compound-containing percutaneouspreparations hitherto known to promote the excellent percutaneouspermeability. In the percutaneous preparation of the present invention,it has also been demonstrated that the system added with a permeationpromoter such as urea, etc. significantly enhances percutaneouspermeability in the bisphosphonate-containing percutaneous system, ascompared to the system added with no promoter. Therefore, percutaneouspermeation enhancers capable of enhancing the percutaneous permeabilityof bisphosphonates can additionally be formulated in the percutaneouspreparation of the present invention, in such a range that does notimpair the objects of the present invention.

Examples of such percutaneous permeation enhancers include terpenes suchas peppermint oil, orange oil, turpentine oil, l-menthol, etc. andnatural essential oil containing the terpenes, dibasic acid diesterssuch as diethyl sebacate, diisopropyl adipate, etc., which are disclosedin the above-mentioned JP-A-5-201879, ethanol and urea, or decyl methylsulfoxide described in the above-mentioned British Patent SpecificationNo. 1,582,694, and the like. Disclosures described in these officialgazettes concerning percutaneous permeation enhancers are herebyincorporated by reference in the specification.

The percutaneous preparation of the present invention containingminodronic acid, etc. shows a good percutaneous permeability especiallyin the acidic region. From a viewpoint of avoiding skin irritation ofthe percutaneous preparation, the preparation is adjusted to be weaklyacidic to neutral, preferably weakly acidic, in the region in contactwith the skin applied. It is thus preferred to add a buffer to asolution composed of the bisphosphonic acid derivative or itspharmaceutically acceptable salt to adjust the pH to 4-7 and formulatethe solution in a base for the percutaneous preparation.

Accordingly, where incadronic acid or its pharmaceutically acceptablesalts are used as the effective ingredients and since these effectiveingredients are water-soluble, it is preferred to add a buffer to theaqueous solution to adjust the pH to approximately 4 to 7 and formulatethe aqueous solution in a base for the percutaneous preparation,especially in a suspension-type base or other base for the percutaneouspreparation. On the other hand, in the case of the percutaneouspreparation containing minodronic acid as the effective ingredient,minodronic acid is previously dissolved in an alkaline solvent and thesolution is neutralized with an acidic solvent to prepare the solutionof minodronic acid. Though minodronic acid is not water-soluble, it hasrevealed that even when neutralized, minodronic acid does notprecipitate as a solid drug but maintains its aqueous solution state andexhibits an excellent percutaneous permeability in the state. Therefore,in making the minodronic acid-containing percutaneous preparation inaccordance with the present invention, it is preferred to prepare aneutralized solution of minodronic acid (pH of about 4 to 7) andformulate the solution in a base for percutaneous administration,especially in a suspension-type base or other bases for percutaneousadministration to adjust the liquid property.

The buffer used herein may be any buffer so long as it is apharmaceutically acceptable buffer and specific examples include organicacids such as citric acid, tartaric acid, succinic acid, malic acid,maleic acid, acetic acid, etc., salts of these organic acids, primary,secondary or tertiary phosphate (e.g., sodium primary phosphate, sodiumsecondary phosphate, etc.), amino acids such as glycine, etc. or saltsof the amino acids, etc., or a mixture thereof. The organic acidsdescribed above also have the properties that are particularly useful informulating in a plaster formulation using a high molecular base.

As described above, the percutaneous preparation of the presentinvention containing minodronic acid, etc. is characterized by itsexcellent percutaneous permeability, targeting to bone tissues and drugretention, and exhibits a significant percutaneous permeabilityespecially in the presence of the suspension-type base. Thus, the“percutaneous preparation” in the percutaneous preparation of thepresent invention containing minodronic acid, etc. may be any type ofpercutaneous preparation so long as the preparation is a type that canachieve these effects. In particular, the preparation may be all typesof external preparations that can achieve the effects of the presentinvention, including a plaster formulation such as a plasterpreparation, a tape preparation, etc., an ointment such as an oil baseointment using white petrolatum as a base, a hydrophilic ointment usingpolyethylene glycol as a base, etc., a gel using carboxyvinyl polymer(Carbopol) as a base (also termed a hydrogel or hydrophilic gelointment), an emulsion using water, oily components and an emulsifyingagent as bases (also termed a cream), a lotion, and the like.Particularly preferred are the types of preparation suitable forcontaining the suspension-type base, for example, the types ofpreparation such as the plaster formulation, ointment, gel, emulsion,lotion, etc. described above. Among other things, the plasterformulation such as a plaster preparation, a tape preparation, etc.,especially a tape preparation is preferred. These percutaneouspreparations can be prepared by applying the procedures for makingpreparations used in the fields of pharmaceutical preparations andcosmetics.

As a typical example of the percutaneous preparation of the presentinvention, a plaster formulation is illustratively explained below.Other external preparations can be prepared in a conventional manner aswill be later described in EXAMPLES, and this illustration is notintended to limit the type of preparation in any way.

The plaster formulation is composed of a support (backing), an adhesivemass having a pressure-sensitive adhesion which is capable of releasingdrugs, and a releasable film for protecting the adhesive mass layer.

In the adhesive mass layer, the effective ingredient minodronic acid,etc. and bases for plaster formulation are formulated. It isparticularly preferred to formulate the suspension-type base as one ofthe bases for plaster formulation.

Specific examples of adhesive components used in the base for plasterformulation are:

(1) natural rubber or synthetic rubber including natural rubber,styrene-butadiene rubber (SBR), polyisoprene rubber, polyisobutylenerubber, styrene-isoprene-styrene block copolymer (SIS),styrene-butadiene-styrene block copolymer (SBS), silicone rubber, oracrylic copolymers (also termed acrylic resins) such as (meth)acrylicacid-(meth)acrylate copolymers, etc.;(2) highly water-absorbing high molecular substances such as acrylicacid-starch, etc.; or,(3) hydrophilic high molecular substances such as polyacrylic acid,sodium polyacrylate, carboxymethyl cellulose (CMC), carboxymethylcellulose sodium salt (CMCNa), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), methyl vinyl ether-maleic anhydride copolymer, sodiumalginate, propylene glycol alginate, pectin, xanthan gum, locust beangum, guar gum, arabiano-galactan, sodium hyaluronate, etc.; and thelike. Rubbers or the like may be used as latex emulsions.

These adhesive components can be formulated solely or in an appropriatecombination of 2 or more. The compounding amount of the adhesivecomponent may vary depending upon difference in plaster preparation ortape preparation, kind of effective ingredients, or kind and amount ofsuspension-type base or other additives formulated, and it is difficultto determine the compounding amount in general. However, it is generallypreferred to formulate the adhesive component in approximately 20 to 99wt %, especially about 30 to about 98.5 wt %, based on the whole (inthis case, the adhesive mass).

As the other additives, there are sludging agents such as gelatin;powdery excipients such as kaolin, bentonite, zinc oxide, etc.;tackifying agents such as petroleum resins, e.g., Quintone (trade name,manufactured by Zeon Corp., aliphatic hydrocarbon resin), Arkon (tradename, manufactured by Arakawa Chemical, Inc.; aliphatic hydrocarbonresin), etc., rosin, hydrogenated rosin, ester gum, terpene resin, etc.;softeners such as polybutene, etc. (polybutene has an adhesive propertyby itself and behaves also as a tackifying agent but is listed as one ofsofteners, since it has an action of softening rubber components withoutadding any other softening agent); surfactants such aspolyoxyethylene-hydrogenated castor oil [e.g., Cremophor (registeredtrademark) RH40 (manufactured by BASF), HCO-40, HCO-60, etc.(manufactured by Nikko Chemicals, Inc.)], polyoxyethylene sorbitanhigher fatty acid esters [e.g., Tween 80 (manufactured by Kanto Kagaku),etc.], sorbitan fatty acid esters, etc.; antiseptics or antioxidants(antiaging agents) such as parabens, e.g., methyl paraben, etc., sorbicacid and salts thereof, butylhydroxyanisole (BHA), dibutylhydroxytoluene(BHT), nordihydroguaiaretic acid, guaiacol esters, etc.; astringentagents such as aluminum chloride, alum, trivalent metal ion-formingsalts such as aluminum alantoinate, etc.; moisturizing agents such asalkaline earth metal salts, etc.; flavoring agents; solvents (organicsolvents such as ethyl acetate, etc., water, aqueous ethanol, etc.); andthe like.

These other additives can be compounded singly or by appropriatelyselecting 2 or more, taking into account adhesive components used.

The compounding amount of these other additives may also vary dependingupon difference in plaster preparation or tape preparation, kind ofeffective ingredients, or kind and amount of suspension-type base orother additives formulated, and it is difficult to determine the amountin general. Generally it is preferred to formulate the additives inapproximately 20 to 99 wt %, especially about 30 to about 98.5 wt %,based on the whole (in this case, the adhesive mass).

To prepare the plaster formulation of the present invention containingminodronic acid, etc., a solution of the effective ingredients isprepared; the liquid property of this solution is adjusted to the pH of4 to 7, if necessary; the adhesive component, the suspension-type baseand other bases for plaster formulation are added thereto; the resultantis uniformly blended and kneaded; the kneaded product is spread onto abacking and, if necessary, dried; a releasable film is laminatedthereon; and the laminate is cut into an adequate size followed bypackaging. These steps are performed by applying those ordinarily usedin the field of plaster formulation. In order to make the preparation ofa uniform adhesive mass easy, for example, it is possible toappropriately set the order of adding or kneading the effectiveingredients, suspension-type base, percutaneous permeation enhancers,buffers, adhesive components and other bases for plaster formulation, orit is also possible to perform treatments like warming, ultrasonication,etc. Spreading is performed in a conventional manner such as, byuniformly applying the kneaded adhesive mass onto a backing or areleasable film in a given thickness. Drying is performed in preparing,e.g., a tape preparation with a less moisture content, where the solventand/or water is vaporized off. However, the solvent such as waterremains in the tape preparation even after drying. As the backing, thereare used cloth, unwoven fabric, plastic films, etc., with particularpreference being plastic films. As the releasable film, there areadvantageously employed release-treated cellophane or plastic films suchas polyethylene film, etc.

It has been demonstrated that the percutaneous preparation of thepresent invention containing minodronic acid, etc. as the effectiveingredient shows a significant percutaneous permeability, especially inthe form of W/O emulsion. When an aqueous solution of incadronic acidsalts, etc., and an emulsion or lotion composed of oily components andemulsifiers are prepared into the percutaneous preparation, the form ofW/O emulsion is preferred. Examples of the emulsifiers used in this caseinclude glycerine fatty acid ester, sorbitan fatty acid ester, propyleneglycol fatty acid ester, polyglycerine fatty acid ester, polyoxyethyleneglycerine fatty acid ester, polyoxyethylene sorbitan fatty acid ester,polyoxyethylene sorbitol fatty acid ester, polyoxyethylene alkyl ether,polyoxyethylene glycol fatty acid ester, polyoxyethylene castor oil, andpolyoxyethylene-hydrogenated castor oil, etc. It is preferred to controlthe emulsion to the HLB of generally from 1 to 8 with these emulsifiersand then provide for use.

In addition to the suspension-type base described above, the oilycomponents further include oily components used for emulsion or lotionpreparations, for example, fatty acid esters, animal and vegetable oils,hydrocarbons, fatty acids, higher alcohol silicone oil, beeswax,paraffin wax, spermaceti, etc.

On the other hand, the percutaneous preparation of the present inventioncomprising at least the bisphosphonic acid derivatives orpharmaceutically acceptable salts thereof, the solubilizing agent forthe bisphosphonic acid derivative and the amphiphilic solubilizingauxiliary agent is characterized by formulating amphiphilic solubilizingauxiliary agent to promote the conversion of the bisphosphonic acidderivative, especially incadronic acid or minodronic acid, orpharmaceutically acceptable salts from the crystalline form (insolubleform) into the soluble form so that the excellent percutaneouspermeability and expression of sustained pharmaceutical effectseventually leading to therapeutic effects at an early stage can beachieved.

In the “bisphosphonic acid derivatives or pharmaceutically acceptablesalts thereof” used in these ingredients-containing percutaneouspreparation of the present invention, which contains the amphiphilicsolubilizing auxiliary agent, the bisphosphonic acid derivatives orpharmaceutically acceptable salts thereof other than incadronic acid orminodronic acid or pharmaceutically acceptable salts thereof can alsoachieve similar effects. In the technique using the amphiphilicsolubilizing auxiliary agent, the effective ingredients are not limitedonly to incadronic acid or minodronic acid or salts thereof. Taking intoaccount the technical idea of the present invention, it is manifest thatnot only the bisphosphonates hitherto known but also bisphosphonates,which will be developed in the future, are usable as the effectiveingredients, so long as they can achieve the objects of the presentinvention.

Therefore, the “bisphosphonic acid derivatives or pharmaceuticallyacceptable salts thereof” referred to in the present invention embraceall bisphosphonate compounds that are synthetic bisphosphonate compoundshaving the methane bisphosphonic acid structure, which is structurallyanalogous to pyrophosphoric acid and stable also in vivo, havebiological actions including a bone resorption inhibitory action,ectopic calcification inhibitory action, etc., are useful as agents forthe treatment of diseases associated with accelerated bone resorption,ectopic calcification, etc., e.g., osteoporosis, Paget's disease ofbone, hypercalcemia accompanied by malignant tumor, etc. and can achievethe effects of the present invention by preparing into a compositioncontaining the amphiphilic solubilizing auxiliary agent of the presentinvention.

Among others, specific examples of the bisphosphonate which isparticularly preferred, include at least one selected from the groupconsisting of alendronic acid, ibandronic acid, incadronic acid,etidronic acid, olpadronic acid, clodronic acid, zoledronic acid,tiludronic acid, neridronic acid, pamidronic acid, risendronic acid,minodronic acid and 1-hydroxy-3-(1-pyrrolidinyl)propylidenebisphosphonicacid as well as salts thereof. Particularly preferred are incadronicacid, minodronic acid or pharmaceutically acceptable salts thereof.

Also in the bisphosphonic acid-containing percutaneous preparation ofthe present invention, it does not hamper to make the percutaneouspreparation using 2 or more effective ingredients selected from thegroup consisting of the bisphosphonic acid derivatives orpharmaceutically acceptable salts thereof.

The compounding amount of the bisphosphonic acid derivatives orpharmaceutically acceptable salts thereof as the effective ingredientsmay be an effective dose pharmacologically required for the percutaneouspreparation. In particular, the compounding amount of the effectiveingredient may vary depending upon kind of the effective ingredient andmay also vary depending upon the kind, amount, etc. of percutaneouspreparation or bases for the percutaneous preparation to be formulated,and cannot be determined in general. Roughly, the compounding amount issuitably from 0.01 to 10 wt %, preferably 0.1 to 5 wt %. Where 2 or moreeffective ingredients are employed, it is preferred to set the totalamount within the above range of the compounding amount.

The “amphiphilic solubilizing auxiliary agent” used in the bisphosphonicacid derivative-containing percutaneous preparation of the presentinvention is intended to mean a substance which is soluble in both waterand oil and promotes the conversion of the bisphosphonic acidderivatives from the crystalline form (insoluble form) to the solubletype. As long as it is an amphiphilic solubilizing auxiliary agent thatcan achieve the objects of the present invention, there is no particularrestriction. Specific examples of the amphiphilic solubilizing auxiliaryagents, which are particularly preferred, are glycerine fatty acidesters such as glyceryl monostearate, glyceryl monolaurate,polyoxyethylene glyceryl monostearate, polyoxyethylene glycerylmonooleate, etc.; polyglycerine fatty acid esters such as hexaglycerylmonostearate, hexaglyceryl monooleate, polyglyceryl isostearate,polyglyceryl distearate, decaglyceryl diisostearate, polyglyceryldioleate, etc.; sorbitan fatty acid esters such as sorbitan monolaurate,etc.; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylenesorbitan monostearate, polyoxyethylene sorbitan monooleate, etc.;polyoxyethylene sorbitol fatty acid esters such as polyoxyethylenesorbitol tetraoleate, etc.; polyoxyethylene alkyl-formaldehyde adductssuch as polyoxyethylene nonyl-formaldehyde adduct, etc.; polyoxyethylenesterol/hydrogenated sterols such as polyoxyethylene phytosterol, etc.;polyethylene glycol fatty acid esters such as polyethylene glycolmonostearate, polyethylene glycol monolaurate, polyethylene glycolmonooleate, polyethylene glycol myristate, polyethylene glycolmonoisostearate, polyethylene glycol distearate, polyethylene glycoldiisostearate, polyethylene glycol dilaurate, polyethylene glycoldioleate, etc.; polyoxyethylene alkyl ethers such as polyoxyethylenelauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearylether, polyoxyethylene behenyl ether, polyoxyethylene synthetic alkylether, polyoxyethylene secondary alkyl ether, polyoxyethylene oleylether, polyoxyethylene tridecyl ether, polyoxyethylene myristyl ether,polyoxyethylene isostearyl ether, polyoxyethylene linolyl ether,polyoxyethylene capryl caproyl ether, etc.; polyoxyethylenepolyoxypropylene alkyl ethers such as polyoxyethylene polyoxypropylenecetyl ether, etc.; polyoxyethylene polyoxypropylene glycols such aspolyoxyethylene polyoxypropylene glycol, etc.; polyoxyethylene alkylphenyl ethers such as polyoxyethylene nonyl phenyl ether, etc.; beeswaxderivatives such as polyoxyethylene sorbitol beeswax, polyethyleneglycol beeswax, etc.; polyoxyethylene alkylamine/fatty acid amides suchas polyoxyethylene stearylamine, polyoxyethylene oleylamine,polyoxyethylene stearic acid amid, etc.; polyoxyethylene alkyl etherphosphoric acid/phosphates such as polyoxyethylene cetyl ether sodiumphosphate, dipolyoxyethylene alkyl ether phosphoric acid,tripolyoxyethylene alkyl ether phosphoric acid, etc.; monofatty acidpolyoxyethylene-hydrogenated castor oil such as lauric acidpolyoxyethylene-hydrogenated castor oil, monoisostearic acidpolyoxyethylene-hydrogenated castor oil, etc.; N-methyl-2-pyrrolidone;acetone; methyl ethyl ketone; methyl isobutyl ketone; triethyl citrate;ethyl acetate; ethyl lactate; triacetine; pantothenyl ethyl ether;ethylene glycol monobutyl ether; dimethyl ether; isopropanolamine;diisopropanolamine; 2-amino-2-methyl-1-propanol;2-amino-2-methyl-1-propanediol; N,N-dimethylacetamide; geranioldenatured alcohol; sucrose octaacetate denatured alcohol; linalylacetate denatured alcohol; benzyl alcohol; butanol; 2-butanol;diethylene glycol; dipropylene glycol; 1,3-butylene glycol; propyleneglycol; propylene carbonate; thioglycolic acid; propionic acid;methanesulfonic acid; glacial acetic acid; lactic acid; butyric acid orichthammol, etc.

Among others, preferred are glycerine fatty acid esters; polyglycerinefatty acid esters; sorbitan fatty acid esters; polyoxyethylene sorbitanfatty acid esters; polyoxyethylene sorbitol fatty acid esters;polyoxyethylene alkyl-formaldehyde adducts; polyoxyethylenesterol/hydrogenated sterols; polyethylene glycol fatty acid esters;polyoxyethylene alkyl ethers; polyoxyethylene polyoxypropylene alkylethers; polyoxyethylene polyoxypropylene glycols; polyoxyethylene alkylphenyl ethers; beeswax derivatives; polyoxyethylene alkylamine/fattyacid amides; polyoxyethylene alkyl ether phosphoric acid/phosphates;monofatty acid polyoxyethylene-hydrogenated castor oil;N-methyl-2-pyrrolidone; acetone; methyl ethyl ketone; or methyl isobutylketone. Among them, particularly preferred are glycerine fatty acidesters; polyethylene glycol fatty acid esters; polyoxyethylene alkylethers; polyoxyethylene polyoxypropylene alkyl ethers; polyoxyethylenepolyoxypropylene glycols; polyoxyethylene alkyl phenyl ethers; beeswaxderivatives; polyoxyethylene alkylamine/fatty acid amides;polyoxyethylene alkyl ether phosphoric acid/phosphates; monofatty acidpolyoxyethylene-hydrogenated castor oil; N-methyl-2-pyrrolidone;acetone; methyl ethyl ketone; or methyl isobutyl ketone.

These amphiphilic solubilizing auxiliary agents may be formulatedsolely, or 2 or more auxiliary agents may be appropriately selected forformulation.

The compounding amount of the amphiphilic solubilizing auxiliary agentmay vary depending upon kind of the bisphosphonic acid derivative as theeffective ingredient, its compounding amount, etc. and cannot bedetermined in general, but roughly it is preferably from 1 to 10 wt %,especially preferably from 3 to 8 wt %, based on the whole preparation.

The “solubilizing agent” used in the present invention is typicallywater since almost all bisphosphonates have excellent solubility inwater. Where, like minodronic acid, the bisphosphonic acid derivative isnot good in water solubility, a solvent for dissolving the bisphosphonicacid derivative, for example, an alkaline solvent such as an alkalinewater, etc. is adopted.

The compounding amount of the solubilizing agent used may vary dependingupon the kind of the bisphosphonic acid contained in the percutaneouspreparation, its solubility or compounding amount per one preparation,the ratio of the soluble form to crystalline form (insoluble form) ofthe drugs in the percutaneous preparation, or the kind or compoundingamount of amphiphilic solubilizing auxiliary agent, and cannot bedetermined in general. Normally it is advantageous to use 0.01 to 10parts by weight, preferably 0.05 to 5 parts by weight of thesolubilizing agent based on 1 part by weight of the bisphosphonic acidderivative, especially in view of the weight ratio of the soluble formto the crystalline form (insoluble form) of the drugs in thepercutaneous preparation set to 1:0.01 to 1:0.9.

In the percutaneous preparation containing the amphiphilic solubilizingauxiliary agent of the present invention, it is preferred to regulatethe weight ratio of the soluble form to the crystalline form (insolubleform) of the drug contained in the percutaneous preparation to 1:0.01 to1:0.9, in addition to incorporation of the amphiphilic solubilizingauxiliary agent. This is especially preferred for more efficientlyconverting the crystalline form (insoluble form) of the drug into thesoluble form by the amphiphilic solubilizing auxiliary agent and thusenhancing sustained percutaneous permeability of the drug to expect thetherapeutic effects at an early stage. The ratio can be regulated byspecifying the compounding ratio of the drug solution, the amphiphilicsolubilizing auxiliary agent and the other bases for percutaneousadministration. Particularly in order to be in the ratio describedabove, it is preferred that 0.01 to 10 parts by weight of thesolubilizing agent is normally used based on 1 part by weight of thebisphosphonic acid derivative, and 1 to 10 parts by weight of theamphiphilic solubilizing auxiliary agent or 0.01 to 50 parts by weightof the suspension-type base chosen as the other base for percutaneousadministration is used based on the whole preparation.

As described above, the “suspension-type base” used herein is notparticularly limited as far as it is a suspension-type base whichsignificantly enhances the percutaneous permeability when the skinpermeation test is conducted using a solution of the bisphosphonic acidderivative. Preferred examples of the suspension-type base aresuspension-type bases such as polyvalent alcohols, higher fatty acidesters having 12 carbon atoms or more, liquid hydrocarbons, vegetableoils, etc., which are given in the percutaneous preparation containingminodronic acid, etc. as the effective ingredient. These suspension-typebases may be used alone or in combination of 2 or more.

Also, the bisphosphonic acid-containing percutaneous preparation of thepresent invention shows a good percutaneous permeability especially inan acidic region. In view of avoiding skin irritation of thepercutaneous preparation, the preparation is preferably adjusted tobecome weakly acidic in the region in contact with the skin applied. Itis therefore preferred to add a buffer to a solution prepared by thebisphosphonic acid derivative or its pharmaceutically acceptable salt toadjust pH from about 4 to about 7 and then formulate the solution in abase for the percutaneous preparation.

The pH adjustment in the bisphosphonic acid-containing percutaneouspreparation of the present invention and buffers used are the same as inthe percutaneous preparation of the present invention containingminodronic acid, etc., using the same buffers.

In the bisphosphonic acid-containing percutaneous preparation of thepresent invention, percutaneous permeation enhancers can be added aswell so that the percutaneous permeation promoting effect of thebisphosphonic acid derivative can be further improved. Accordingly, itis possible to formulate percutaneous permeation enhancers for thebisphosphonates in the percutaneous preparation of the presentinvention, in addition to the amphiphilic solubilizing auxiliary agent,within such a range that does not impair the objects of the invention.

As such percutaneous permeation enhancers, there are terpenes such aspeppermint oil, orange oil, turpentine oil, l-menthol, etc. and naturalessential oil containing the terpenes, dibasic acid diesters such asdiethyl sebacate, diisopropyl adipate, etc., which are disclosed in theabove-mentioned JP-A-5-201879, ethanol and urea, or decyl methylsulfoxide described in the above-mentioned British Patent SpecificationNo. 1,582,694, and the like. Disclosures described in these officialgazettes concerning percutaneous permeation enhancers are herebyincorporated by reference in the specification.

Since the concentration of the drug contained in the preparation in asolution state or the concentration of the drug dissolved in themoisture of skin decreases accompanied by percutaneous absorption of thedrug through the skin as stated above, the “percutaneous preparation”containing the amphiphilic solubilizing auxiliary agent of the presentinvention promotes dissolution of the drug in a crystalline state by theaction of the amphiphilic solubilizing auxiliary agent and eventuallyexhibits an excellent percutaneous permeability.

Thus, the “percutaneous preparation” of the percutaneous preparation ofthe present invention containing the amphiphilic solubilizing auxiliaryagent wherein the bisphosphonates are the effective ingredients may beany percutaneous preparation, so long as it takes the preparation formthat can achieve the effects described above by adding the amphiphilicsolubilizing auxiliary agent. As described above, the percutaneouspreparation includes all types of external preparations that can achievethe effects of the present invention, including a plaster formulation,an ointment, a gel, an emulsion, a lotion, etc. These percutaneouspreparations can be prepared by applying the procedures for makingpreparations used in the fields of pharmaceutical preparations andcosmetics.

As a typical example of the percutaneous preparation of the presentinvention, a plaster formulation is illustratively explained below.Other external preparations can be prepared in a conventional manner aswill be later described in EXAMPLES, and this illustration is notintended to limit the type of preparation in any way.

The plaster formulation is composed of a support (backing), an adhesivemass having a pressure-sensitive adhesion which is capable of releasingdrugs, and a releasable film for protecting the adhesive mass layer.

In the adhesive mass layer, a solution composed of the bisphosphonicacid derivative or its pharmaceutically acceptable salt and thesolubilizing agent for the bisphosphonic acid derivative, theamphiphilic solubilizing auxiliary agent and other bases for thepercutaneous preparation are formulated. It is particularly preferred toformulate the suspension-type base as one of the bases for the plasterformulation. When incadronate or minodronic acid is used as theeffective ingredient, the percutaneous preparation is preferably in theform of a plaster preparation or a tape preparation, more preferably inthe form of a tape preparation.

As the adhesive component used in the bases for plaster formulation,there are the natural or synthetic rubbers, highly water-absorbing highmolecular substances, hydrophilic high molecular substances, etc., givenas examples for the percutaneous preparation containing minodronic acid,etc. These rubbers or the like can be used as latex emulsions.

These adhesive components can be formulated solely or in an appropriatecombination of 2 or more. The compounding amount of the adhesivecomponent may vary depending upon difference in plaster preparation ortape preparation, kind of effective ingredients, or kind and amount ofsuspension-type base or other additives formulated, and it is difficultto determine the compounding amount in general. However, it is generallypreferred to formulate the adhesive component in approximately 20 to 99wt %, especially about 30 to about 98.5 wt %, based on the whole (inthis case, the adhesive mass).

As the other additives, there are the sludging agents, softeners,surfactants, antiseptics or antioxidants, astringent agents,moisturizing agents, flavoring agents, solvents, etc., which are givenas examples hereinbefore.

These other additives can be compounded singly or by appropriatelyselecting 2 or more, taking into account adhesive components used.

The compounding amount of these other additives may also vary dependingupon difference in plaster preparation or tape preparation, kind ofeffective ingredients, or kind and amount of suspension-type base orother additives formulated, and it is difficult to determine the amountin general. However, it is generally preferred to formulate theadditives in approximately 20 to 99 wt %, especially about 30 to about98.5 wt %, based on the whole (in this case, the adhesive mass).

To prepare the plaster formulation of the present invention containingthe bisphosphonic acid derivative; a solution is prepared using thebisphosphonic acid derivative and the solubilizing agent; the liquidproperty of this solution is adjusted to the pH of from 4 to 7, ifnecessary; the amphiphilic solubilizing auxiliary agent, the adhesivecomponent and other bases for the plaster formulation are added thereto;the resultant is uniformly blended and kneaded; the kneaded product isspread onto a baking and, if necessary, dried; a releasable film islaminated thereon; and the laminate is cut into an adequate sizefollowed by packaging. These steps are performed by applying thoseordinarily used in the field of plaster formulation, as described above.

EXAMPLES

Hereinafter the present invention will be described in more detail bydescription of EXAMPLES. However, it is needless to say that the presentinvention is not limited to the description of these EXAMPLES.

Example 1

Ointment

After 5.0 parts of lanolin, 5.0 parts of cetostearyl alcohol and 80parts of white petrolatum were melted on a water bath, a blend of 20%aqueous solution containing 0.5 part of incadronate, 5.0 parts ofN-methyl-2-pyrrolidone and 4.5 parts of liquid paraffin was added to themolten mixture. The resultant was uniformly kneaded while warming (about80° C.). After discontinuing warming, the resultant was made fullyhomogeneous to provide an ointment.

Example 2

Cream

After 5.0 parts of cetanol, 2.0 parts of stearic acid, 1.0 part ofsorbitan monostearate and 1.0 part of polyoxyethylene sorbitanmonostearate were melted on a water bath, a blend of 20% aqueoussolution containing 1.0 part of incadronate, 5.0 parts ofN-methyl-2-pyrrolidone and 9.0 parts of liquid paraffin was added to themolten mixture. The resultant was uniformly kneaded and maintained atabout 75° C. A solution previously prepared by 0.1 part of methylparaoxybenzoate and butyl paraoxybenzoate in a sufficient quantity ofdistilled water and warming at 80° C. was added to the kneaded mixture,followed by uniformly kneading while warming. After discontinuingwarming, the resultant was made fully homogeneous to provide a cream.

Example 3

Plaster Formulation (Tape, Incadronate and N-Methyl-2-Pyrrolidone)

A blend of 20% aqueous solution containing 2.0 parts of incadronate asthe effective ingredient, 5.0 parts of N-methyl-2-pyrrolidone, 2.5 partsof α-monoisostearyl glyceryl ether, 5.0 parts of isopropyl myristate and1.0 part of sorbitan fatty acid ester was added to 40.0 parts ofstyrene-isoprene-styrene block copolymer, 34.5 parts of terpene resinand 10.0 parts of aliphatic hydrocarbon resin, and a sufficient quantityof ethyl acetate was added thereto. The resultant was uniformly mixed toform an adhesive mass. The adhesive mass was uniformly applied onto areleasable film followed by drying with warm air. A backing film waslaminated and transferred thereon to provide a tape preparation.

Example 4

Plaster Formulation (Tape Preparation, Minodronic Acid andN-Methyl-2-Pyrrolidone)

A blend of 20% aqueous solution containing 2.0 parts of minodronic acidas the effective ingredient prepared using a 2-fold mol of 2M sodiumhydroxide aqueous solution, 5.0 parts of N-methyl-2-pyrrolidone, 2.5parts of α-monoisostearyl glyceryl ether, 5.0 parts of isopropylmyristate and 1.0 part of sorbitan fatty acid ester was added to 40.0parts of styrene-isoprene-styrene block copolymer, 34.5 parts of terpeneresin and 10.0 parts of aliphatic hydrocarbon resin, and a sufficientquantity of ethyl acetate was added thereto. The resultant was uniformlymixed to form an adhesive mass. The adhesive mass was uniformly appliedonto a releasable film followed by drying with warm air. A backing filmwas laminated and transferred thereon to provide a tape preparation.

Example 5

Plaster Formulation (Tape Preparation, Minodronic Acid andPolyoxyethylene Lauryl Ether)

A blend of 20% aqueous solution containing 2.0 parts of minodronic acidas the effective ingredient prepared using a 2-fold mol of 2M sodiumhydroxide aqueous solution, 5.0 parts of polyoxyethylene lauryl ether,2.5 parts of α-monoisostearyl glyceryl ether, 5.0 parts of isopropylmyristate and 1.0 part of sorbitan fatty acid ester was added to 40.0parts of styrene-isoprene-styrene block copolymer, 34.5 parts of terpeneresin and 10.0 parts of aliphatic hydrocarbon resin, and a sufficientquantity of ethyl acetate was added thereto. The resultant was uniformlymixed to form an adhesive mass. The adhesive mass was uniformly appliedonto a releasable film followed by drying with warm air. A backing filmwas laminated and transferred thereon to provide a tape preparation.

Example 6

Plaster Formulation (Tape Preparation, Minodronic Acid and PolyethyleneGlycol Monostearate)

A blend of 20% aqueous solution containing 2.0 parts of minodronic acidas the effective ingredient prepared using a 2-fold mol of 2M sodiumhydroxide aqueous solution, 5.0 parts of polyethylene glycolmonostearate, 2.5 parts of α-monoisostearyl glyceryl ether, 5.0 parts ofisopropyl myristate and 1.0 part of sorbitan fatty acid ester was addedto 40.0 parts of styrene-isoprene-styrene block copolymer, 34.5 parts ofterpene resin and 10.0 parts of aliphatic hydrocarbon resin, and asufficient quantity of ethyl acetate was added thereto. The resultantwas uniformly mixed to form an adhesive mass. The adhesive mass wasuniformly applied onto a releasable film followed by drying with warmair. A backing film was laminated and transferred thereon to provide atape preparation.

Example 7

Plaster Formulation (Tape Preparation, Minodronic Acid and Methyl EthylKetone)

A blend of 20% aqueous solution containing 2.0 parts of minodronic acidas the effective ingredient prepared using a 2-fold mol of 2M sodiumhydroxide aqueous solution, 5.0 parts of methyl ethyl ketone, 2.5 partsof α-monoisostearyl glyceryl ether, 5.0 parts of isopropyl myristate and1.0 part of sorbitan fatty acid ester was added to 40.0 parts ofstyrene-isoprene-styrene block copolymer, 34.5 parts of terpene resinand 10.0 parts of aliphatic hydrocarbon resin, and a sufficient quantityof ethyl acetate was added thereto. The resultant was uniformly mixed toform an adhesive mass. The adhesive mass was uniformly applied onto areleasable film followed by drying with warm air. A backing film waslaminated and transferred thereon to provide a tape preparation.

Example 8

Plaster Formulation (Tape Preparation, Alendronate andN-Methyl-2-Pyrrolidone)

A blend of 20% aqueous solution containing 2.0 parts of alendronate asthe effective ingredient, 5.0 parts of N-methyl-2-pyrrolidone, 2.5 partsof α-monoisostearyl glyceryl ether, 5.0 parts of isopropyl myristate and1.0 part of sorbitan fatty acid ester was added to 40.0 parts ofstyrene-isoprene-styrene block copolymer, 34.5 parts of terpene resinand 10.0 parts of aliphatic hydrocarbon resin, and a sufficient quantityof ethyl acetate was added thereto. The resultant was uniformly mixed toform an adhesive mass. The adhesive mass was uniformly applied onto areleasable film followed by drying with warm air. A backing film waslaminated and transferred thereon to provide a tape preparation.

Example 9

Plaster Formulation (Tape Preparation, Minodronic Acid and MethylIsobutyl Ketone)

A blend of 20% aqueous solution containing 2.0 parts of minodronic acidas the effective ingredient prepared using a 2-fold mol of 2M sodiumhydroxide aqueous solution, 5.0 parts of methyl isobutyl ketone, 2.5parts of α-monoisostearyl glyceryl ether, 5.0 parts of isopropylmyristate and 1.0 part of sorbitan fatty acid ester was added to 40.0parts of styrene-isoprene-styrene block copolymer, 34.5 parts of terpeneresin and 10.0 parts of aliphatic hydrocarbon resin, and a sufficientquantity of ethyl acetate was added thereto. The resultant was uniformlymixed to form an adhesive mass. The adhesive mass was uniformly appliedonto a releasable film followed by drying with warm air. A backing filmwas laminated and transferred thereon to provide a tape preparation.

The present invention is useful in terms of providing the percutaneouspreparation of incadronic acid, minodronic acid or pharmaceuticallyacceptable salts thereof for the first time, which could not be expectedespecially from conventional bisphosphonate percutaneous preparations,and providing the percutaneous preparation which promotes thepercutaneous permeability of bisphosphonates and has excellent sustainedrelease by formulating the solubilizing agent for the bisphosphonatesand the amphiphilic solubilizing auxiliary agent in the percutaneousbisphosphonate preparation. The percutaneous preparation of the presentinvention is useful since the preparation can reduce burdens on thepatient with disease associated with percutaneous permeability,accelerated bone resorption, ectopic calcification, etc. and can achievethe therapeutic effects by percutaneous administration of incadronate,minodronic acid, etc. surely in a short period of time, withoutdeteriorating the patient's compliance even when administered over along period of time.

These effects were verified by the following examples of experiments.

Experiment 1

Percutaneous Absorption Test of ¹⁴C-Incadronate Aqueous Solution

[Test Method]

—Method of Preparing ¹⁴C-Incadronate Aqueous Solution—

That is, 5 mg of ¹⁴C-labeled incadronic acid bulk powder was weighed and0.5N sodium hydroxide was added to become 0.069 ml, which was used as¹⁴C-incadronate labeled product containing an amount equivalent to 6.073mg. By adding 538.3 μl of purified water to the labeled product, anaqueous solution of 10 mg/ml of ¹⁴C-incadronate was prepared. To 200 μlof the ¹⁴C-incadronate aqueous solution, 1800 μl of non-radioactive 1%incadronate aqueous solution was added for dilution.

—Method for Administration and Dose—

The rat abdominal hair was shaved and a round cell (made of acryl, 20 mmin diameter) was fixed on the skin with a medical adhesive. The¹⁴C-incadronate aqueous solution was poured into the cell (10 mg/kg) andcapped to prevent the solution from leaking. During the test, the ratwas fixed dorsally under urethane anesthesia.

—Measurement of Radioactivity—

Bone tissue specimens were burnt in a tissue combustion equipment andthe radioactivity was counted by a scintillation counter.

Experimental Results

The experimental results are shown in TABLE 1.

TABLE 1 24 Hours after Percutaneous Administration Concentration 48.3 +10.8 in the humerus (μg/g) Concentration 28.3 + 6.1 in the costa (μg/g)—Discussions—

As is clear from the foregoing results, incadronate rapidly moved ontothe bone by percutaneous route and shows very high concentration in thebone tissues in 24 hours after the administration.

Experiment 2

In Vitro Skin Permeation Test

[Test Method]

In Wistar male rat (7 weeks old) the abdominal hair was shaved and theskin at that area was taken in a diameter of 2 cm. The skin was mountedin a two-chamber diffusion cell. A test drug solution was infused intothe donor side and into the acceptor side an isotonic phosphate buffer(pH 7.4) was infused. Samples were collected from the acceptor side withpassage of time. The drug content in the samples collected wasquantitatively determined by high performance liquid chromatography, andthe accumulated permeation amount per unit area was calculated.Comparison was made using as a positive control the skin, from which thestratum corneum having the barrier function in percutaneous permeationwas removed (stripped skin).

Formulation Example Nos. 1 through 12

In solution formulation Nos. 1 through 12, the compounding componentsand amounts are shown in TABLES 2 and 3.

Using 10 parts of crotamiton and 5 parts of surfactant polyoxyethylenesorbitan monooleate having HLB 15 in the case of O/W emulsion, andlikewise using 84 parts of crotamiton and 5 parts of sorbitan monooleatehaving HLB 4.3 in the case of W/O emulsion, 84 parts and 10 parts ofpurified water were added to 1 part of incadronate, respectively, foremulsification to prepare the O/W and W/O emulsions.

TABLE 2 Formulation Example No. 1 2 3 4 5 6 7 8 Incadronate 1 1 1 1 1 11 1 Water 99 64 86 96 89 — — — Ethanol — 30 10 — 10 — — — l-Menthol — 53 3 — — — — Britton-Robinson — 99 — — Buffer (pH 3) Britton-Robinson — —99 — Buffer (pH 6) Britton-Robinson — — — 99 Buffer (pH 9)

TABLE 3 Formulation Example No. 9 10 11 12 Incadronate 1 1 1 1 Water 94 — — — Urea 5 — — — O/W Emulsion — 99  — — W/O Emulsion — — 99  — Liquidparaffin — — — 99 

Experimental Results

The skin permeation test results described above are shown in TABLE 4.

TABLE 4 Formulation Accumulated Permeation Example No. Amount for 8Hours (μg/cm²)  1 (stripped skin) 1653.9 + 106.6  1 (intact skin) 461.4 + 61.7  2 (intact skin)  954.5 + 243.7  3 (intact skin)  971.5 +122.9  4 (intact skin)  894.8 + 123.9  5 (intact skin)  964.3 + 75.9  6(intact skin)  749.4 + 101.1  7 (intact skin)  568.7 + 43.7  8 (intactskin)  510.7 + 63.7  9 (intact skin)  892.8 + 144.6 10 (intact skin) 624.8 + 157.0 11 (intact skin) 1004.5 + 131.0 12 (intact skin) 1536.1 +92.3[Discussions]

As is evident from the experimental results described above, it wasdemonstrated that the stratum corneum of skin functions as a barrier fordrug permeation in the percutaneous preparation of 1% incadronateaqueous solution; in the formulations added with 30% ethanol+5%l-menthol, 10% ethanol+3% l-menthol, 3% l-menthol and 5% urea, thepercutaneous permeation promoting effect by about twice was shown in thesystem with any percutaneous permeation enhancer, when compared to the1% incadronate aqueous solution; a tendency to increase the percutaneouspermeation amount was noted as the liquid property of the formulationswas declined toward the acidic property; the W/O emulsions showedsignificantly superior percutaneous permeation promoting effects thanthe O/W emulsions; in the suspension-type formulations using thesuspension-type bases such as liquid paraffin, etc., the formulationsshowed the percutaneous permeability surprisingly far superior to thesystem added with the percutaneous permeation enhancers or to the W/Oemulsion system, which was comparable to the stripped skin.

Experiment 3

In Vitro Skin Permeation Test

[Test Method]

In a manner similar to EXPERIMENT 2, the abdominal hair of Wistar malerat (7 weeks old) was shaved and the skin at that area was taken in adiameter of 2 cm. The skin was mounted in a two-chamber diffusion cell.The percutaneous preparations of EXAMPLE 3 described above, COMPARATIVEEXAMPLE 1 described below and CONTROL 1 described below as well asEXAMPLE 4 described above, COMPARATIVE EXAMPLE 2 described below andCONTROL 2 described below A were infused into the donor side and intothe acceptor side an isotonic phosphate buffer (pH 7.4) was infused.Samples were collected from the acceptor side with passage of time. Thedrug content in the samples collected was quantitatively determined byhigh performance liquid chromatography, and the accumulated permeationamount per unit area was calculated.

Comparative Example 1

Plaster Formulation (Tape Preparation, Incadronate and Decyl MethylSulfoxide)

A 20% aqueous solution containing 2.0 parts of incadronate as theeffective ingredient, 5.0 parts of decyl methyl sulfoxide, 2.5 parts ofα-monoisostearyl glyceryl ether, 5.0 parts of isopropyl myristate and1.0 part of sorbitan fatty acid ester were blended. After the blend wasadded to 40.0 parts of styrene-isoprene-styrene block copolymer, 34.5parts of terpene resin and 10.0 parts of aliphatic hydrocarbon resin, asufficient quantity of ethyl acetate was added thereto and the resultantwas uniformly mixed to form an adhesive mass. The adhesive mass wasuniformly applied onto a releasable film followed by drying with warmair. A backing film was laminated and transferred thereon to provide atape preparation.

Control 1

Plaster Formulation (Tape Preparation, Incadronate)

A 20% aqueous solution containing 2.0 parts of incadronate as theeffective ingredient, 2.5 parts of α-monoisostearyl glyceryl ether, 5.0parts of isopropyl myristate and 1.0 part of sorbitan fatty acid esterwere blended. After the blend was added to 40.0 parts ofstyrene-isoprene-styrene block copolymer, 34.5 parts of terpene resinand 15.0 parts of aliphatic hydrocarbon resin, a sufficient quantity ofethyl acetate was added thereto and the resultant was uniformly mixed toform an adhesive mass. The adhesive mass was uniformly applied onto areleasable film followed by drying with warm air. A backing film waslaminated and transferred thereon to provide a tape preparation.

Comparative Example 2

Plaster Formulation (Tape Preparation, Minodronic Acid and Decyl MethylSulfoxide)

A 20% aqueous solution containing 2.0 parts of minodronic acid as theeffective ingredient, 5.0 parts of decyl methyl sulfoxide, 2.5 parts ofα-monoisostearyl glyceryl ether, 5.0 parts of isopropyl myristate and1.0 part of sorbitan fatty acid ester were blended. After the blend wasadded to 40.0 parts of styrene-isoprene-styrene block copolymer, 34.5parts of terpene resin and 10.0 parts of aliphatic hydrocarbon resin, asufficient quantity of ethyl acetate was added thereto and the resultantwas uniformly mixed to form an adhesive mass. The adhesive mass wasuniformly applied onto a releasable film followed by drying with warmair. A backing film was laminated and transferred thereon to provide atape preparation.

Control 2

Plaster Formulation (Tape Preparation, Minodronic Acid)

A 20% aqueous solution containing 2.0 parts of minodronic acid as theeffective ingredient, 2.5 parts of α-monoisostearyl glyceryl ether, 5.0parts of isopropyl myristate and 1.0 part of sorbitan fatty acid esterwere blended. After the blend was added to 40.0 parts ofstyrene-isoprene-styrene block copolymer, 34.5 parts of terpene resinand 15.0 parts of aliphatic hydrocarbon resin, a sufficient quantity ofethyl acetate was added thereto and the resultant was uniformly mixed toform an adhesive mass. The adhesive mass was uniformly applied onto areleasable film followed by drying with warm air. A backing film waslaminated and transferred thereon to provide a tape preparation.

Experimental Results

In the results of the skin permeation test in vitro described above, theaccumulated permeation amount for 8 hours (μg/cm²) are shown in TABLE 5.

TABLE 5 Accumulated Permeation Amount for 8 Hours EXAMPLE No. (μg/cm²)EXAMPLE 3 20.64 + 2.03 (tape preparation: incadronate, (intact skin)N-methyl-2-pyrrolidone) COMPARATIVE EXAMPLE 1 11.73 + 0.46 (tapepreparation: incadronate, (intact skin) decyl methyl sulfoxide) CONTROL1  1.24 + 1.21 (tape preparation: incadronate, (intact skin) noamphiphilic solubilizing auxiliary agent) EXAMPLE 4 47.00 + 6.58 (tapepreparation: minodronic (intact skin) acid, N-methyl-2-pyrrolidone)COMPARATIVE EXAMPLE 2 11.15 + 1.14 (tape preparation: minodronic (intactskin) acid, decyl methyl sulfoxide) CONTROL 2  0.93 + 0.09 (tapepreparation: minodronic (intact skin) acid, no amphiphilic solubilizingauxiliary agent)[Discussions]

As is evident also from the experimental results described above, thepercutaneous preparation of the present invention containing theamphiphilic solubilizing auxiliary agent exhibited far superiorpercutaneous permeability through the preparations, as compared to theplaster formulation system containing decyl methyl sulfoxide known tohave the percutaneous permeation promoting effect on thebisphosphonates.

Experiment 4

In Vitro Skin Permeation Test

[Test Method]

In a manner similar to EXPERIMENT 2, the abdominal hair of Wistar malerat (7 weeks old) was shaved and the skin at that area was taken in adiameter of 2 cm. The skin was mounted in a two-chamber diffusion cell.The percutaneous preparations of EXAMPLES 5 through 7 described above aswell as EXAMPLE 8 described above, COMPARATIVE EXAMPLE 3 described belowand CONTROL 3 described below A were infused into the donor side andinto the acceptor side an isotonic phosphate buffer (pH 7.4) wasinfused. Samples were collected from the acceptor side with passage oftime. The drug content in the samples collected was quantitativelydetermined by high performance liquid chromatography, and theaccumulated permeation amount per unit area was calculated. Theexperimental results in EXAMPLES containing the amphiphilic solubilizingauxiliary agent are shown in TABLE 6 and the experimental resultsexamined on the other drugs are shown in TABLE 7.

Comparative Example 3

Plaster Formulation (Tape Preparation, Alendronate and Decyl MethylSulfoxide)

A 20% aqueous solution containing 2.0 parts of alendronate as theeffective ingredient, 5.0 parts of decyl methyl sulfoxide, 2.5 parts ofα-monoisostearyl glyceryl ether, 5.0 parts of isopropyl myristate and1.0 part of sorbitan fatty acid ester were blended. After the blend wasadded to 40.0 parts of styrene-isoprene-styrene block copolymer, 34.5parts of terpene resin and 10.0 parts of aliphatic hydrocarbon resin, asufficient quantity of ethyl acetate was added thereto and the resultantwas uniformly mixed to form an adhesive mass. The adhesive mass wasuniformly applied onto a releasable film followed by drying with warmair. A backing film was laminated and transferred thereon to provide atape preparation.

Control 3

Plaster Formulation (Tape Preparation, Alendronate)

A 20% aqueous solution containing 2.0 parts of alendronate as theeffective ingredient, 2.5 parts of α-monoisostearyl glyceryl ether, 5.0parts of isopropyl myristate and 1.0 part of sorbitan fatty acid esterwere blended. After the blend was added to 40.0 parts ofstyrene-isoprene-styrene block copolymer, 34.5 parts of terpene resinand 15.0 parts of aliphatic hydrocarbon resin, a sufficient quantity ofethyl acetate was added thereto and the resultant was uniformly mixed toform an adhesive mass. The adhesive mass was uniformly applied onto areleasable film followed by drying with warm air. A backing film waslaminated and transferred thereon to provide a tape preparation.

Experimental Results

In the results of the skin permeation test in vitro described above, theaccumulated permeation amount for 8 hours (μg/cm²) are as follows.

TABLE 6 Accumulated Permeation Amount for EXAMPLE No. 8 Hours (μg/cm²)EXAMPLE 5 29.96 + 2.90 (tape preparation: minodronic (intact skin) acid,polyoxyethylene lauryl ether) EXAMPLE 6 23.08 + 5.70 (tape preparation:minodronic (intact skin) acid, polyethylene glycol monostearate) EXAMPLE7 28.31 + 6.18 (tape preparation: minodronic (intact skin) acid, methylethyl ketone)

TABLE 7 Accumulated Permeation Amount for EXAMPLE No. 8 Hours (μg/cm²)EXAMPLE 8 8.56 + 2.60 (tape preparation: alendronate, (intact skin)N-methyl-2-pyrrolidone) COMPARATIVE EXAMPLE 3 2.54 + 0.79 (tapepreparation: alendronate, (intact skin) decyl methyl sulfoxide) CONTROL3 0.18 + 0.08 (tape preparation: alendronate, (intact skin) noamphiphilic solubilizing auxiliary agent)[Discussions]

As is evident also from the experimental results described above, it wasdemonstrated that various amphiphilic solubilizing auxiliary agentsshowed an excellent percutaneous permeability; the system using theseamphiphilic solubilizing auxiliary agents exhibited a more excellentpercutaneous permeability with the same drug than those when decylmethyl sulfoxide was used as a percutaneous permeation enhancer, even inthe case of using the other bisphosphonates such as alendronate, etc.;and the percutaneous permeability by the aforesaid preparation usingminodronic acid as the effective ingredient (EXAMPLE 4) was superior byseveral times as compared to the preparation using alendronate as theeffective ingredient.

INDUSTRIAL APPLICABILITY

As is clear from the foregoing description, the percutaneous preparationin accordance with the present invention shows an excellent percutaneouspermeability. By this excellent characteristic, burdens on the patientare thus reduced as compared to the case where other preparation formsusing the bisphosphonic acid derivative as the effective ingredient areadministered, so that the patient's compliance is not deteriorated evenin the administration over a prolonged period of time. In addition,therapeutic effects can be achieved in a short period of time.Therefore, it becomes possible to provide the preparations withexpectation of such excellent effects.

1. A plaster formulation comprising: (a) minodronic acid, orpharmaceutically acceptable salts thereof, at from 0.1 to 5 weightpercent (b) 0.05 to 5 parts by weight of a solubilizing agent based on 1part by weight of the minodronic acid or salt thereof, (c)N-methyl-2-pyrrolidone at from 3 to 8 weight percent, and (d) astyrene-isoprene-styrene block copolymer as an adhesive component. 2.The plaster formulation according to claim 1, wherein the plasterformulation is in the form of a tape.
 3. A method for treating diseasesassociated with accelerated bone resorption or ectopic calcification,comprising administering an effective amount of minodronic acidcontained in the plaster formulation according to claim 1 to a patientin need thereof.